Electrical signals enter the hippocampus through the dentate gyrus, which acts as a "gate" to seizure activity. The granule cells of the dentate gyrus normally prevent seizures from propagating into the hippocampus. After status epilepticus (SE), which can lead to chronic epilepsy, certain classes of GABAergic inhibitory interneurons are preferentially killed, and both inhibitory and excitatory circuits are progressively reorganized. Mossy fiber sprouting, a well-established form of epilepsy-associated reorganization, appears to lead to new excitatory circuits that are thought to be masked by high levels of inhibition. The proposed experiments will address whether a focal lesion of inhibitory interneurons, when present concurrently with mossy fiber sprouting after SE, will unmask the effects of the new excitatory circuits and generate interictal spikes and seizure-like activity. The neurotoxin SSP-saporin will be used to lesion selectively inhibitory interneurons in the dentate, and the kainate model of temporal lobe epilepsy will be used to produce mossy fiber sprouting and epileptogenesis. With whole-cell and extracellular recordings in hippocampal slices, mlPSC frequency will be analyzed to study the functional loss of interneurons after the SSP-saporin injections, and responses to extracellular stimulation will be investigated to test seizure susceptibility of the dentate gyrus. Immunocytochemistry and Timm staining will be used to assess interneuron loss and mossy fibers sprouting, respectively. The proposed experiments should reveal how the presence of multiple changes in hippocampal circuitry may contribute to epileptogenesis.